Multiple sclerosis (“MS”) is an inflammatory autoimmune disorder of the central nervous system (Compston and Coles, Lancet 372, 1502-17 (2008)). With a prevalence of about one in 1000, MS is the most common cause of neurological disability in young adults (Polman and Uitdehaag, BMJ 321, 490-4 (2000)). MS involves engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration (see, e.g., Compston and Coles, 2008). These sequential processes underlie a clinical course characterized by episodes with recovery, episodes leaving persistent deficits, and secondary progression. Id.
The goal of MS treatment is to reduce the frequency and severity of relapses, prevent disability arising from disease progression, and promote tissue repair (Compston and Coles, 2008). The primary approach to MS treatment is modulation or suppression of the immune system. Currently available MS drugs include interferon beta-1a (e.g., AVONEX and REBIF), interferon beta-1b (e.g., BETASERON), glatiramer acetate (e.g., COPAXONE), mitoxantrone (e.g., NOVANTRONE), and natalizumab (e.g., TYSABRI). Another promising new drug for MS is alemtuzumab (CAMPATH-1H).
Alemtuzumab is a humanized monoclonal antibody directed against CD52, a protein widely distributed on the surface of lymphocytes and monocytes but with unknown function. Alemtuzumab has been used to treat B-cell chronic lymphocytic leukaemia. A single pulse of treatment leads to a rapid, profound, and prolonged lymphopenia. Cell numbers recover but at varying rates; CD4+ T cells are particularly slow to recover, remaining depleted for at least five years (Coles et al., Journal of Neurology 253, 98-108 (2006)). A phase 2 trial (CAMMS-223 study group; Coles et al., N. Engl. J. Med. 359, 1786-1801 (2008)) has shown that alemtuzumab is highly effective in treating early relapsing-remitting multiple sclerosis. This drug reduces the risk of disease activity and accumulation of disability by over 70% compared to interferon-beta in patients with early relapsing-remitting multiple sclerosis. The principal adverse effect is autoimmunity, arising in the setting of T cell lymphopenia months to years after dosing. About 20%-30% of patients develop thyroid autoimmunity, mainly Graves' disease (Coles et al., Lancet 354, 1691-1695 (1999)), and 3% have immune thrombocytopenia (ITP) (Coles et al., 2008). Single cases of Goodpasture's disease, autoimmune neutropenia (Coles et al., Journal of Neurology 253, 98-108 (2006)), and autoimmune haemolytic anaemia (unpublished observation) also have been observed. In addition, a further 5.5% of patients develop sustained non-thyroid autoantibodies without clinical disease (Coles et al., 2006). The timing and spectrum of autoimmunity after alemtuzumab is similar to that seen in other examples of “reconstitution autoimmunity” in other clinical contexts; for example, autoimmune thyroid disease and autoimmune cytopenias also predominate months to years after hematopoietic stem cell transplantation or antiretroviral treatment of HIV (Chen et al., Medicine (Baltimore) 84, 98-106 (2005); Daikeler and Tyndall, Best. Pract. Res. Clin. Haematol. 20, 349-360 (2007); Jubault et al., J. Clin. Endocrinol. Metab. 85, 4254-4257 (2000); Ting, Ziegler, and Vowels, Bone Marrow Transplant. 21, 841-843 (1998); Zandman-Goddard and Shoenfeld, Autoimmun. Rev. 1, 329-337 (2002)).
While autoimmunity arising in the context of lymphopenia is well recognized in animal models, it is rarely encountered and, hence, difficult to study in humans. Most lymphopenic subjects do not develop autoimmunity, suggesting that additional factors are involved (Krupica et al., Clin Immunol 120, 121-128 (2006)). It remains unclear what those additional factors are. Depletion of T regulatory cells has been considered as one factor, as seen in the murine colitis and gastritis models (Alderuccio et al., J Exp. Med 178, 419-426 (1993); McHugh et al., J. Immunol 168, 5979-5983 (2002); Powrie et al., Int. Immunol 5, 1461-1471 (1993); Sakaguchi et al., J Immunol 155, 1151-1164 (1995)). However, it has been observed that T regulatory cells are increased after alemtuzumab in human patients and thereafter return to normal levels (Cox et al., Eur J Immunol 35, 3332-3342 (2005)). This observation has since been replicated (Bloom et al., Am J Transplant. 8, 793-802 (2008)) and is in keeping with other experimental lymphopenic models (de Kleer, I. et al., Blood 107, 1696-1702 (2006); Zhang, H. et al., Nat Med 11, 1238-1243 (2005)).